Synthesis and Antibacterial Activity of 8-Ketoberberine Derivatives

Abstract Natural berberine (BBR) exhibits good antimicrobial efficacy, however, its limited bioavailability greatly hinder its clinical application. In this study, 18 novel lipophilic C-8-substituted BBR prodrugs were synthesized and tested for in vitro antimicrobial activity against four common clinical pathogens, and the inhibitory mechanism was further investigated with respect to the ability of bacterial membrane formation, cell permeability, hydrophobicity, and self-cohesion. Our results found that compound 14 showed the best activity with MIC (minimum inhibitory concentration) = 15.62 µg/mL and MBC (minimum bactericidal concentration) = 31.25 µg/mL against Staphylococcus aureus (ATCC 29213) and Listeria monocytogenes (4b G). Mechanism studies showed that compound 14 has a significant inhibiting over 60% of bacterial biofilm formation at a concentration of 0.5 MIC and enhancing cell membrane permeability by 40%. Meanwhile, compound 14 can interact with the cell membrane, exposing its hydrophobic region and reducing the intercellular self-coagulation index to about 20%. The study suggests that novel compound 14 enhanced the antibacterial effect by significantly reducing bacterial surface hydrophobicity and self-cohesion and disrupting bacterial biofilm. In summary, we have created a series of 8-ketoberberine derivatives, which opens new prospects for BBR derivatives in the treatment of bacterial infections.